Draft Recommendation Statement

This opportunity for public comment expired on December 26, 2018 at 8:00 PM EST

Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF.
The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.

Recommendations made by the USPSTF are independent of the U.S. government.
They should not be construed as an official position of the Agency for Healthcare
Research and Quality or the U.S. Department of Health and Human Services.

Table of Contents

Draft: Preface

The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decisionmaking to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms

Draft: Rationale

Importance

An estimated 1.1 million persons in the United States are currently living with HIV, and more than 700,000 persons have died from AIDS since the first cases were reported in 1981.1 In 2016, an estimated 39,782 new diagnoses of HIV infection occurred in the United States; 81% (32,131) of these new diagnoses were among males and 19% (7,529) were among females.1 Though treatable, HIV infection is not curable and has significant health consequences.

Identification of Risk Status

Although the USPSTF found inadequate evidence that specific risk assessment tools can accurately identify persons at high risk of HIV acquisition, it found adequate epidemiologic data on risk factors that can be used to identify persons at high risk of acquiring HIV infection.

Benefits of Preventive Medication

The USPSTF found convincing evidence that PrEP is of substantial benefit in decreasing the risk of HIV infection in persons at high risk of HIV infection, either via sexual acquisition or through injection drug use. The USPSTF also found convincing evidence that adherence to PrEP is highly correlated with its efficacy in preventing the acquisition of HIV infection.

Harms of Preventive Medication

The USPSTF found adequate evidence that PrEP is associated with small harms, including renal and gastrointestinal adverse effects.

USPSTF Assessment

The USPSTF concludes with high certainty that there is a substantial net benefit from the use of PrEP to reduce the risk of acquisition of HIV infection in persons at high risk of HIV infection.

Draft: Clinical Considerations

Patient Population Under Consideration

This recommendation applies to persons who are not infected with HIV and are at high risk of HIV infection.

Assessment of Risk

Although the USPSTF found no well-validated, accurate tools to assess risk of HIV acquisition, epidemiologic data, U.S. Public Health Services (USPHS) guidelines,2 and enrollment criteria for clinical trials provide guidance on detecting persons who may be at high risk. Persons at risk for HIV infection include men who have sex with men, persons at risk via heterosexual contact, and persons who inject drugs. Within these groups, certain risk factors or behaviors (outlined below) can place persons at high risk of HIV infection.

It is important to note that men who have sex with men and heterosexual persons who are in a mutually monogamous relationship with a partner who has recently tested negative for HIV are not considered to be at high risk. Additionally, all persons being considered for PrEP must have a recently documented negative HIV test.

The USPSTF recommends the following persons be considered for PrEP:

Men who have sex with men, are sexually active, and have one of the following characteristics:

Heterosexual women and men who are sexually active and have one of the following characteristics:

A serodiscordant sex partner (i.e., a sex partner living with HIV)

Inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk (e.g., a person who inject drugs or bisexual partner)

A recent STI with syphilis or gonorrhea

Persons who inject drugs and have one of the following characteristics:

Share drug injection equipment

Are at risk of sexual acquisition of HIV (see above)

Persons who engage in commercial sex work or are trafficked for sex work constitute another group at high risk of HIV acquisition, and should be considered for PrEP based on the criteria outlined above. Sexually active bisexual men are at risk of HIV acquisition, and should be evaluated for PrEP according to the criteria for men who have sex with men and heterosexual men outlined above.

Transgender women and men who are sexually active may be at increased risk of HIV acquisition, and should be considered for PrEP based on the criteria outlined above. Although trials of PrEP enrolled few transgender women and no trials have been conducted among transgender men, PrEP has been shown to reduce the risk of HIV acquisition during receptive and insertive anal and vaginal sex. Therefore, its use may be considered in all persons (cis and transgender) at high risk of sexual acquisition of HIV.

Consistent use of condoms decreases risk of HIV acquisition by approximately 80%3 and also decreases the risk of other STIs. However, condoms are often used inconsistently by sexually active adults.4 PrEP should be considered as an option to reduce the risk of HIV acquisition in persons who use condoms inconsistently, while continuing to encourage and support consistent condom use.

Evidence shows that the risk of HIV transmission in serodiscordant couples is quite low when the seropositive partner is being treated with antiretroviral therapy and has a suppressed viral load.5, 6 It is not known whether PrEP use further decreases the risk of HIV transmission when a seropositive partner is being treated with antiretroviral therapy and has a documented undetectable viral load.

It is important to note that the risk of acquisition of HIV infection lies on a continuum. Additionally, risk behavior should be interpreted in the context of a community’s or network’s HIV prevalence; that is, risk behaviors in a high-prevalence setting carry a higher risk of acquiring HIV infection than the same behavior in a low-prevalence setting. The threshold of HIV prevalence below which PrEP has insignificant net benefit is not known.

Preventive Medication

Once-daily oral treatment with combined tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) is the only formulation of PrEP approved by the U.S. Food and Drug Administration (FDA) for use in the United States in persons at risk of sexual acquisition of HIV infection. However, several studies reviewed for this recommendation statement found that tenofovir alone was also effective as PrEP, and USPHS guidelines note that, given this trial data, tenofovir alone can be considered as an alternative regimen for high-risk heterosexual men and women and persons who inject drugs.2

According to its product label, TDF-FTC may be considered for use as PrEP during pregnancy.7 No trials of PrEP included pregnant women; however, pregnancy is associated with an increased risk of HIV acquisition.8 USPHS guidelines recommend shared decisionmaking for pregnant women who are considering starting or continuing PrEP during pregnancy.

Adolescents at high risk of HIV acquisition could benefit from PrEP, and TDF-FTC is approved by the FDA for use as PrEP in adolescents who weigh at least 35 kg.6 However, no randomized clinical trials of PrEP enrolled adolescents. Limited data suggest that PrEP use is not associated with significant adverse events in adolescents but may be associated with slightly less bone growth than would be expected.9 The USPSTF suggests that clinicians weigh all these factors when considering PrEP use in adolescents at high risk of HIV acquisition. Additionally, clinicians need to be aware of any local laws and regulations that may apply when providing PrEP to an adolescent minor.

Additional Approaches to Prevention

Several additional approaches to decreasing risk of HIV acquisition are also available. Consistent use of condoms decreases risk of HIV acquisition by approximately 80%3 and reduces the risk of other STIs. The USPSTF recommends intensive behavioral counseling to reduce behaviors associated with increased risk of STIs and HIV acquisition and to increase condom use among adolescents and adults at increased risk of STIs.10 The Centers for Disease Control and Prevention (CDC) has made several recommendations, including abstinence, reducing one’s number of sexual partners, and consistent condom use, to decrease risk of STIs, including HIV. The CDC also recommends syringe service programs (i.e., needle exchange programs) to reduce the risk of HIV acquisition and transmission among persons who inject drugs. The CDC’s recommendations are available at www.cdc.gov/std/prevention/default.htm and https://www.cdc.gov/hiv/risk/ssps.html. The Community Preventive Services Task Force has also issued several recommendations on the prevention of HIV and other STIs, which are available at https://www.thecommunityguide.org/topic/hivaids-stis-and-pregnancy. Post-exposure prophylaxis, started as soon as possible after a possible exposure event, can also decrease the risk of HIV infection.

Screening for HIV infection to detect undiagnosed cases and antiretroviral treatment of persons living with HIV to suppress viral load are both important approaches to decreasing the risk of HIV transmission at the population level, while also benefiting the individual living with HIV. The USPSTF recommends screening for HIV infection in adolescents and adults ages 15 to 65 years, younger adolescents and older adults at increased risk, and all pregnant women.11

Draft: Other Considerations

Implementation

The first step in implementing PrEP is identifying persons at high risk of HIV acquisition who may benefit from PrEP. It is important that clinicians routinely take a sexual and injection drug use history for all their patients. If a person is identified as potentially belonging to a high-risk group, then further discussion can identify behaviors that may make that person an appropriate candidate for PrEP.

The CDC provides a complete discussion of implementation considerations for PrEP, including baseline and followup testing and monitoring, time to achieving protection, and discontinuing PrEP, which is available at www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf. A few of the particularly important points regarding the provision of PrEP are outlined below.

Before prescribing PrEP, clinicians should exclude acute or chronic HIV infection through medical history and HIV testing. The two-drug antiretroviral regimen used in PrEP is not an effective treatment for HIV infection, and its use in persons living with HIV can lead to the emergence of, or selection for, drug-resistant HIV infection. It is also generally suggested that renal function testing, serologic testing for hepatitis B and C virus, testing for other STIs, and pregnancy testing (when appropriate) be conducted at the time of or just prior to initiating PrEP. Ongoing followup and monitoring, including HIV testing every 3 months, is also suggested. The time from initiation of PrEP to achieving protection against HIV infection is unknown. Pharmacokinetic data suggest that maximum levels of tenofovir disphosphate (the active form of tenofovir) is reached in 7 days in rectal tissue, and in 20 days in blood (peripheral blood mononuclear cells) and vaginal tissue.2 Patients can continue PrEP as long as high risk of HIV acquisition persists. Patients may discontinue PrEP for several reasons, including personal preference, decreased risk of HIV, or medication side effects.

PrEP does not reduce the risk of other STIs. Consistent use of condoms decreases risk of HIV acquisition by approximately 80%3 and reduces the risk of other STIs. Promoting consistent condom use is an important component of a successful PrEP program.

Given the strong connection between adherence to PrEP and its effectiveness in preventing HIV acquisition, adherence support is an important component of providing PrEP. Components of adherence support include establishing trust and open communication with patients, patient education, reminder systems for taking medication, and attention to medication side effects and having a plan to address them. Adherence support is especially important in populations who have been shown to have lower adherence to PrEP, such as young persons and racial/ethnic minorities.12-14

Research Needs and Gaps

Research is needed to develop and validate tools for identifying persons at high risk of HIV acquisition who would benefit from PrEP. When developed and validated, risk assessment instruments should include those populations most at risk for HIV infection, particularly racial/ethnic minorities such as black/African American and Hispanic/Latino populations.

Research is needed on different drug regimens and dosing strategies for PrEP. Several trials investigating different antiretroviral drugs or drug regimens for use as PrEP are ongoing.

Research is needed on factors associated with adherence to PrEP and methods to increase uptake and adherence, especially in populations with low adherence such as younger persons (adolescents) and racial/ethnic minorities.

Trials or demonstration projects of PrEP in U.S. populations of heterosexual persons, persons who inject drugs, and transgender women and men are needed to better quantify effectiveness in those populations. Research is needed on the safety and effectiveness of PrEP during pregnancy and breastfeeding. Research is also needed on the long-term safety and effectiveness of PrEP.

Draft: Discussion

Burden of Disease

Since the first cases of AIDS were reported in 1981, more than 700,000 persons in the United States have died from AIDS.1 The CDC estimates that 1.1 million persons in the United States are currently living with HIV infection,1 including an estimated 15% who are unaware of their infection.15 The annual number of new HIV infections in the United States has decreased from about 42,000 new cases in 2011 to 40,000 each year from 2013 to 2016.1 Of these new cases of HIV infection in 2016, 81% were in males and 19% were in females.1 Groups disproportionately affected by HIV infection in the United States include men who have sex with men, black/African American populations, and Hispanic/Latino populations. From 2011 to 2016, HIV incidence rates increased in persons ages 25 to 29 years and in American Indian/Alaska Native and Asian populations.1

PrEP is currently not used in many persons at high risk of HIV infection. The CDC estimates that approximately 1.2 million persons were eligible for PrEP in 2015 (492,000 men who sex with men, 115,000 persons who inject drugs, and 624,000 heterosexual adults)16 and an estimated 78,360 persons used PrEP in 2016.17

Scope of Review

For this recommendation, the USPSTF commissioned a systematic review18 of the evidence on the benefits of PrEP for HIV with oral TDF or TDF-FTC and whether the benefits vary by risk group, population subgroup, or regimen or dosing strategy; the diagnostic accuracy of risk assessment tools to identify persons at high risk of HIV acquisition; the rates of adherence to PrEP in primary care settings; the association between adherence and effectiveness of PrEP; and the harms of PrEP when used for HIV prevention.

Effectiveness of Risk Assessment

The USPSTF found seven studies that evaluated risk assessment tools developed in U.S. cohorts for predicting incident HIV infection—six in men who have sex with men19-24 and one in persons who inject drugs.25 The USPSTF found no studies evaluating tools for predicting risk of HIV infection in men and women at increased risk of HIV infection via heterosexual contact in U.S. cohorts. In those studies that reported it, discrimination of the risk prediction instrument was moderate, with area under the receiver operating characteristic curve of 0.66 to 0.72. However, each study evaluated a different risk prediction tool. Some instruments were not validated in independent cohorts, and several instruments were developed and validated using older (i.e., prior to 2000) cohorts. Most of the studies of risk prediction tools in men who have sex with men were developed in predominantly white populations, and two studies found that several of the instruments performed more poorly in black men who have sex with men (area under the receiver operating characteristic curve, 0.51 to 0.62).23, 24 All tools are predicated on knowing that a person belongs to an HIV risk group; no tool has been designed to predict incident HIV infection in persons not already identified as belonging to an HIV risk category.18

The USPSTF considered several factors in its assessment of risk of HIV acquisition, including the prevalence of HIV infection within a group and the risk that a specific behavior or action will lead to acquisition of HIV. The prevalence of HIV infection among men who have sex with men, persons who inject drugs and the overall population age 13 years and older is estimated to be 12.4%, 1.9%, and 0.4%, respectively.15 In terms of risk of HIV acquisition from specific behaviors, receptive anal intercourse without a condom and needle-sharing injection drug use carry the highest risk, while insertive anal intercourse, receptive penile-vaginal intercourse, and insertive penile-vaginal intercourse carry lower but not negligible risks of acquiring HIV from a partner or source who is seropositive for HIV.3

Effectiveness of Preventive Medication

The USPSTF found 12 randomized clinical trials that evaluated the effect of PrEP versus placebo12, 26-35 or no PrEP36 on the risk of HIV acquisition. One trial was of fair quality because of an open-label design; all other trials were of good quality. Duration of followup ranged from 4 months to 4 years. Six trials28-30, 33-35 enrolled men and women at increased risk of HIV infection via heterosexual contact, four trials12, 26, 32, 36 enrolled men who have sex with men or transgender women, one trial27 enrolled both men who have sex with men and high-risk women, and one trial31 enrolled persons who inject drugs. No trial enrolled pregnant women or persons younger than age 18 years. Three trials12, 31, 33 evaluated TDF 300 mg, seven trials26-28, 32, 34, 35 evaluated TDF 300 mg/FTC 200 mg, one trial36 evaluated TDF 245 mg/FTC 200 mg, and two trials29, 30 included arms for both TDF 300 mg alone and TDF 300 mg/FTC 200 mg. PrEP was prescribed daily in 11 trials,12, 27-36 and dosing was intermittent or event-driven in three trials (including two trials that also included daily dosing arms).26-28 Seven trials were conducted in Africa,27-30, 33-35 one in Thailand,31 two in Europe or Canada,26, 36 and one in the United States,12 and one trial was multinational.32 All trials of persons at high risk of HIV infection via heterosexual contact were conducted in Africa, and the only trial of persons who inject drugs was conducted in Thailand.31 All trials of PrEP also included behavioral and adherence counseling, and most specified that they provided condoms to all trial participants.

One small trial reported no cases of HIV infection.28 In the other 11 trials, the rate of HIV infection ranged from 1.4% to 7.0% over 4 months to 4 years in participants randomized to placebo or no PrEP, and 0% to 5.6% in those randomized to PrEP. In a meta-analysis of these trials, PrEP was associated with reduced risk of HIV infection compared with placebo or no PrEP (relative risk [RR], 0.46 [95% CI 0.33 to 0.66]; absolute risk reduction, -2.0% [95% CI, -2.8% to -1.2%]) after 4 months to 4 years.18

PrEP was effective across population subgroups defined by HIV risk category. There were no statistically significant differences in estimates of effectiveness for PrEP versus placebo or no PrEP in risk of HIV acquisition when trials were stratified according to whether they enrolled men who have sex with men or transgender women (although the number of transgender persons in trials was small) (four trials; RR, 0.23 [95% CI, 0.08 to 0.62]), men and women at increased risk of HIV infection via heterosexual contact (five trials; RR, 0.54 [95% CI, 0.31 to 0.97]), or persons who inject drugs (one trial; RR, 0.52 [95% CI, 0.29 to 0.92]; p=0.43 for interaction).18

In a meta-analysis of the trials reviewed by the USPSTF, both TDF-FTC and TDF alone appeared equally effective in decreasing the risk of HIV acquisition (eight trials; RR, 0.44 [95% CI, 0.27 to 0.72] vs. five trials; RR, 0.49 [95% CI, 0.28 to 0.84], respectively; p=0.65 for interaction).18

Three included trials investigated alternative dosing strategies (using PrEP less frequently than daily [intermittent dosing] or before and after HIV exposure events [event-driven” dosing]).26-28 One trial28 reported no HIV events and a second27 did not report results for intermittent/event-driven and daily dosing of PrEP arms separately. The third trial (Intervention Préventive de l’Exposition aux Risques avec et pour les Gays [IPERGAY]) found that event-driven PrEP dosing was associated with a lower risk of HIV infection than placebo in men who have sex with men (RR, 0.14 [95% CI, 0.03 to 0.63]).26 In this trial, men randomized to PrEP took an average of about four doses of PrEP per week (15 doses per month), so it is uncertain whether this finding would apply to less frequent use or on-demand dosing. Also, tenofovir accumulates more rapidly in anal tissue than vaginal tissue,37 so this study may not be generalizable to other risk groups.

The USPSTF also evaluated the evidence on the relationship between adherence to PrEP and its effectiveness in decreasing risk of HIV infection. Methods for evaluating adherence differed between studies, and included patient diaries and self-report, pill counts, adherence monitoring devices, drug levels (e.g., plasma or dried blood spots), and prescription fill data.

In the trials of PrEP reviewed for this recommendation, adherence to PrEP ranged from 30% to 100%, and the relative risk of HIV infection in participants randomized to PrEP, compared with placebo or no PrEP, ranged from 0.95 to 0.07.18 In a stratified analysis of these studies, a strong interaction (p<0.00001) between level of adherence and effectiveness of PrEP was found, with higher levels of adherence associated with greater reduction in risk of HIV acquisition (adherence ≥70%: six trials; RR, 0.27 [95% CI, 0.19 to 0.39]; adherence >40% to <70%: three trials; RR, 0.51 [95% CI, 0.38 to 0.70]; and adherence ≤40%: two trials; RR, 0.93 [95% CI, 0.72 to 1.20]).18 There was also a strong association (p<0.0005) between adherence and effectiveness when adherence was analyzed as a continuous variable in a meta-regression.18

Since the effectiveness of PrEP is closely tied to adherence, the USPSTF reviewed the evidence on levels of adherence to PrEP in U.S.-relevant settings. Three observational studies of U.S. men who have sex with men found adherence to PrEP (based on tenofovir-diphosphate levels in dried blood spot sampling consistent with ≥4 doses/week) of 66% to 90% over 4 to 48 weeks.14, 38, 39 Two observational studies of younger men who have sex with men (mean ages, 20 and 16 years) reported lower rates of adherence to PrEP (again based on blood spot sampling) of approximately 50% at 12 weeks, decreasing to 34% and 22% at 48 weeks.40, 41 Two studies in U.S. men who have sex with men found that self-reported adherence was highly correlated with adherence based on dried blood spot sampling.12, 13

Multivariate analysis of the largest U.S. PrEP implementation study to date39 found that black race was associated with lower adherence compared with white race (adjusted odds ratio, 0.28 [95% CI, 0.12 to 0.64]). Having stable housing or having receptive anal sex without a condom with two or more partners was associated with increased adherence (AOR, 2.02 [95% CI, 1.14 to 3.55] and 1.82 [95% CI, 1.14 to 2.89], respectively). There was no association between age, educational attainment, income level, health insurance status, and alcohol or drug use and adherence. Only 1.4% of participants enrolled were transgender women, so it is not possible to draw conclusions about adherence to PrEP in this population. The USPSTF found no data (no studies) on factors associated with adherence to PrEP in U.S. populations of persons who inject drugs or persons at high risk of HIV infection via heterosexual contact.18

Potential Harms of Risk Assessment and Preventive Medication

The randomized clinical trials that investigated the effectiveness of PrEP had 4 months to 4 years of followup, and also reported on the harms of PrEP.12, 26-36, 42-49 In a pooled analysis of these studies, PrEP was associated with increased risk of renal adverse events (primarily grade 1 or greater serum creatinine elevation) versus placebo (12 trials; absolute risk difference, 0.60% [95% CI, 0.09% to 1.11%]). There was no clear difference in risk of renal adverse events when trials were stratified according to use of TDF or TDF-FTC. Serious renal events were rare and no trial reported a difference between PrEP and placebo in risk of serious renal events or withdrawals due to renal events.18 Six trials27-29, 42-44 evaluated whether renal adverse events while using PrEP were persistent. Three studies29, 42, 44 reported a return to normal serum creatinine levels after cessation of PrEP and two others27, 28, 45 reported normalization of creatinine level without PrEP cessation. In one other trial, the Bangkok Tenofovir Study of persons who inject drugs, there were seven cases of grade 2 or greater creatinine elevation, and all but one case resolved following PrEP cessation.43

PrEP was associated with increased risk of gastrointestinal adverse events (primarily nausea) versus placebo (12 trials; ARD, 3.20% [95% CI, 0.38 to 6.02%]). The risk of gastrointestinal adverse events was increased for both TDF and TDF-FTC,18 with risk diminishing over time in three trials.31, 32, 34 Serious gastrointestinal events were rare in trials reporting this outcome, with no differences between PrEP and placebo.30, 32-36

Tenofovir exposure is associated with bone loss,34, 46-48 which could result in increased fracture risk. A meta-analysis of seven studies that reported on fractures, using both study data and updated fracture data reported to the FDA, found a not statistically significant trend toward increased risk of fracture in persons randomized to PrEP versus placebo. This result was also heavily weighted by the one study of PrEP in persons who inject drugs, which reported a relatively high fracture rate.18

One concern about PrEP is that its use may lead to persons at risk of HIV acquisition not using condoms or engaging in other behaviors that could increase their risk of STIs (i.e., behavioral risk compensation). In meta-analyses of the studies reviewed by the USPSTF, there was no differences between PrEP and placebo or no PrEP in risk of syphilis (four trials; RR, 1.08 [95% CI, 0.98 to 1.18]), gonorrhea (five trials; RR, 1.10 [95% CI, 0.86 to 1.40]), chlamydia (five trials; RR, 1.04 [95% CI, 0.90 to 1.20]), or combined bacterial STIs (two trials; RR, 1.15 [95% CI, 1.00 to 1.32]).18 All of the trials except for one were blinded, which could affect risk of STIs if participants who don’t know if they are taking PrEP or placebo behave differently than those who know they are taking PrEP. In the one open-label trial, there was also no statistically significant association between PrEP and the risk of STIs.36

An additional concern is the possibility that the use of antiretroviral drugs as PrEP could lead to the development or acquisition of drug-resistant HIV infection. In eight trials of PrEP using TDF or TDF-FTC, 1.1% (3/282) of patients newly diagnosed with HIV infection while taking PrEP had tenofovir resistance mutations.26, 29-33, 35, 36 In six trials of PrEP with TDF-FTC, 8.0% (14/174) of patients newly diagnosed with HIV infection while taking PrEP had emtricitabine resistance mutations.26, 29, 30, 32, 34-36 There was one case of multiple resistance mutations, which is included in both the total number of tenofovir and emtricitabine resistance mutations. Most resistance mutations (one of two tenofovir resistance mutations, eight of 13 emtricitabine resistance mutations, and the one case with multiple resistance mutations, or 63% of total cases) occurred in persons who were already infected with HIV upon trial enrollment but were not recognized as such. This highlights the importance of excluding persons with acute or chronic HIV infection prior to initiating PrEP. The USPSTF found no data on the effect of resistance mutations on clinical outcomes.

No trial of PrEP enrolled pregnant women, and women who became pregnant during the course of the trial were withdrawn from participation. Three trials reported on pregnancy outcomes in women who were withdrawn from PrEP because of pregnancy.28, 35, 49 Among women who became pregnant in the trials, PrEP was not associated with increased risk of spontaneous abortion. One trial, the Partners PrEP trial, also found no differences between PrEP and placebo in pregnancy rate, risk of preterm birth, birth anomalies, or postpartum infant mortality.49

Estimate of Magnitude of Net Benefit

The USPSTF found convincing evidence that PrEP is of substantial benefit in decreasing the risk of HIV infection in persons at high risk of HIV acquisition. The USPSTF also found convincing evidence that adherence to PrEP is highly correlated with its efficacy in preventing the acquisition of HIV infection; thus adherence to PrEP is central to realizing its benefit. The USPSTF found adequate evidence that PrEP is associated with small harms, including renal and gastrointestinal adverse effects. The USPSTF concludes with high certainty that the magnitude of benefit of PrEP with oral tenofovir-based therapy to reduce the risk of acquisition of HIV infection in persons at high risk is substantial.

How Does Evidence Fit With Biological Understanding?

HIV is a ribonucleic acid (RNA) retrovirus that infects immune cells, in particular CD4+ T cells. Antiretroviral agents interfere with one of several steps in viral infection and replication, such as HIV entry into CD4+ cells, reverse transcription of viral RNA into deoxyribonucleic acid, integration of the viral genome into the host genome, and assembly of HIV proteins and RNA into new virus.50 TDF and FTC are both reverse transcriptase inhibitors, and have favorable safety profiles. TDF achieves particularly high concentrations in rectal tissue, and FTC achieves high concentrations in the female genital tract.51 The possibility of using PrEP to prevent HIV transmission was suggested by the success of antiretroviral agents in preventing mother-to child transmission of HIV and their use as post-exposure prophylaxis,52-54 and was demonstrated in several animal models, including one that showed FTC and TDF decreased the risk of rectal transmission of simian immunodeficiency virus in macaques.55

Draft: Recommendations of Others

The 2017 USPHS guidelines recommends PrEP with TDF-FTC as one HIV prevention option for men who have sex with men, persons at risk via heterosexual contact, and persons who inject drugs, who are at substantial risk of HIV infection, with TDF alone as an alternative for persons at risk via heterosexual contact and persons who inject drugs, who are at substantial risk.2 2016 World Health Organization guidance recommends offering PrEP containing TDF as an additional prevention choice for persons at substantial risk (provisionally defined as HIV incidence higher than 3 cases per 100 person-years) of HIV infection, as part of HIV prevention approaches.56